tbuckley/cabot-search huggingface dataset:
Prehospital Tranexamic Acid for Severe Trauma
Authors: Russell L Gruen, Biswadev Mitra, Stephen A Bernard, Colin J McArthur, Brian Burns, Dashiell C Gantner, Marc Maegele, Peter A Cameron, Bridget Dicker, Andrew B Forbes, Sally Hurford, Catherine A Martin, Stefan M Mazur, Robert L Medcalf, Lynnette J Murray, Paul S Myles, Sze J Ng, Veronica Pitt, Stephen Rashford, Michael C Reade, Andrew H Swain, Tony Trapani, Paul J Young
Journal: New England Journal of Medicine (2023)

Whether prehospital administration of tranexamic acid increases the likelihood of survival with a favorable functional outcome among patients with major trauma and suspected trauma-induced coagulopathy who are being treated in advanced trauma systems is uncertain.We randomly assigned adults with major trauma who were at risk for trauma-induced coagulopathy to receive tranexamic acid (administered intravenously as a bolus dose of 1 g before hospital admission, followed by a 1-g infusion over a period of 8 hours after arrival at the hospital) or matched placebo. The primary outcome was survival with a favorable functional outcome at 6 months after injury, as assessed with the use of the Glasgow Outcome Scale-Extended (GOS-E). Levels on the GOS-E range from 1 (death) to 8 ("upper good recovery" [no injury-related problems]). We defined survival with a favorable functional outcome as a GOS-E level of 5 ("lower moderate disability") or higher. Secondary outcomes included death from any cause within 28 days and within 6 months after injury.A total of 1310 patients were recruited by 15 emergency medical services in Australia, New Zealand, and Germany. Of these patients, 661 were assigned to receive tranexamic acid, and 646 were assigned to receive placebo; the trial-group assignment was unknown for 3 patients. Survival with a favorable functional outcome at 6 months occurred in 307 of 572 patients (53.7%) in the tranexamic acid group and in 299 of 559 (53.5%) in the placebo group (risk ratio, 1.00; 95% confidence interval [CI], 0.90 to 1.12; P = 0.95). At 28 days after injury, 113 of 653 patients (17.3%) in the tranexamic acid group and 139 of 637 (21.8%) in the placebo group had died (risk ratio, 0.79; 95% CI, 0.63 to 0.99). By 6 months, 123 of 648 patients (19.0%) in the tranexamic acid group and 144 of 629 (22.9%) in the placebo group had died (risk ratio, 0.83; 95% CI, 0.67 to 1.03). The number of serious adverse events, including vascular occlusive events, did not differ meaningfully between the groups.Among adults with major trauma and suspected trauma-induced coagulopathy who were being treated in advanced trauma systems, prehospital administration of tranexamic acid followed by an infusion over 8 hours did not result in a greater number of patients surviving with a favorable functional outcome at 6 months than placebo. (Funded by the Australian National Health and Medical Research Council and others; PATCH-Trauma ClinicalTrials.gov number, NCT02187120.).
Oxygen concentration modulates colibactin production
Authors: Nadège Bossuet, Cécile Guyonnet, Camille V Chagneau, Min Tang-Fichaux, Marie Penary, Dorian Loubet, Priscilla Branchu, Eric Oswald, Jean-Philippe Nougayrede
Journal: Gut Microbes (2023)

Up to 25% of the E. coli strains isolated from the feces of healthy humans harbor the pks genomic island encoding the synthesis of colibactin, a genotoxic metabolite. Evidence is accumulating for an etiologic role of colibactin in colorectal cancer. Little is known about the conditions of expression of colibactin in the gut. The intestine is characterized by a unique oxygenation profile, with a steep gradient between the physiological hypoxic epithelial surface and the anaerobic lumen, which favors the dominance of obligate anaerobes. Here, we report that colibactin production is maximal under anoxic conditions and decreases with increased oxygen concentration. We show that the aerobic respiration control (ArcA) positively regulates colibactin production and genotoxicity of pks+ E. coli in response to oxygen availability. Thus, colibactin synthesis is inhibited by oxygen, indicating that the pks biosynthetic pathway is adapted to the anoxic intestinal lumen and to the hypoxic infected or tumor tissue.
Lipid nanoparticles-loaded with toxin mRNA represents a new strategy for the treatment of solid tumors
Authors: Yasmin Granot-Matok, Assaf Ezra, Srinivas Ramishetti, Preeti Sharma, Gonna Somu Naidu, Itai Benhar, Dan Peer
Journal: Theranostics (2023)

Background and rationale: Cancer therapy have evolved remarkably over the past decade, providing new strategies to inhibit cancer cell growth using immune modulation, with or without gene therapy.Specifically, suicide gene therapies and immunotoxins have been investigated for the treatment of tumors by direct cancer cell cytotoxicity.Recent advances in mRNA delivery also demonstrated the potential of mRNA-based vaccines and immune-modulators for cancer therapeutics by utilizing nanocarriers for mRNA delivery.Methods: We designed a bacterial toxin-encoding modified mRNA, delivered by lipid nanoparticles into a B16-melanoma mouse model.Results: We showed that local administration of LNPs entrapping a modified mRNA that encodes for a bacterial toxin, induced significant anti-tumor effects and improved overall survival of treated mice.Conclusions: We propose mmRNA-loaded LNPs as a new class of anti-tumoral, toxin-based therapy.
The landscape of abnormal pathway activation confers COVID-19 patients' molecular sequelae earlier than clinical phenotype
Authors: Xiuli Zhang, Yuan Sh, Jierong Dong, Zhongqing Chen, Feitong Hong
Journal: Theranostics (2023)

Rationale:The 2019 coronavirus disease (COVID-19) pandemic poses a significant threat to human health.After SARS-CoV-2 infection, major clinical concerns are organ damage and possible sequelae.Methods: In this study, we analyzed serum multi-omics data based on population-level, including healthy cohort, non-COVID-19 and COVID-19 covered different severity cohorts.We applied the pseudo-SpatioTemporal Consistency Alignment (pST-CA) strategy to correct for individualized disease course differences, and developed pseudo-deterioration timeline model and pseudo-recovery timeline model based on the "severe index" and "course index".Further, we comprehensively analyzed and discussed the dynamic damage signaling in COVID-19 deterioration and/or recovery, as well as the potential risk of sequelae. Results:The deterioration and course models based on the pST-CA strategy can effectively map the activation of blood molecular signals on cellular, pathway, functional and disease phenotypes in COVID-19 deterioration and throughout the disease course.The models revealed the neurological, cardiovascular, and hepatic toxicity present in SARS-CoV-2.The abundance of differentially expressed proteins and the activity of upstream regulators were comprehensively analyzed and evaluated to predict possible target drugs for SARS-CoV-2.On molecular docking simulation analysis, it was further demonstrated that blocking CEACAM1 is a potential therapeutic target for SARS-CoV-2.Conclusions: Clinically, the risk of organ failure and death in COVID-19 patients rises with increasing number of infections.Individualized sequelae prediction for patients and assessment of individualized intervenable targets and available drugs in combination with the upstream regulator analysis results are of great clinical value.
Fenfluramine: A Review in Dravet and Lennox-Gastaut Syndromes
Authors: James E. Frampton
Journal: Drugs (2023)

Fenfluramine (Fintepla®) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients. Emerging in infancy and childhood, respectively, Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are severe developmental and epileptic encephalopathies. They are characterized by seizures that are frequently 'pharmacoresistant' [i.e. cannot be controlled by ≥ 2 anti-seizure medications (ASMs)] and that, along with cognitive and behavioural comorbidities, can have a major impact on the quality of life of patients (and their caregivers/family members) as they grow. Fenfluramine (Fintepla®) is an oral ASM with a distinctive dual mechanism of action, that is used at low doses. In clinical trials in patients with DS or LGS, adding fenfluramine to the existing ASM regimen produced significant and sustained reductions in pharmacoresistant seizures and was associated with clinically meaningful improvements in aspects of everyday executive functioning (EF; i.e. the ability to regulate cognition, emotions and/or behaviour). Importantly, there was no evidence of the heart complications previously observed with the use of high doses of fenfluramine as an appetite suppressant. Adjunctive fenfluramine is an effective and generally well-tolerated treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.
Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma
Authors: Martin F. Kaiser, Andrew Hall, Katrina Walker, Amy Sherborne, Ruth M. De Tute, Nicola Newnham, Sadie Roberts, Emma Ingleson, Kristian Bowles, Mamta Garg, Anand Lokare, Christina Messiou, Richard S. Houlston, Graham Jackson, Gordon Cook, Guy Pratt, Roger G. Owen, Mark T. Drayson, Sarah R. Brown, Matthew W. Jenner
Journal: Journal of Clinical Oncology (2023)

The multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra-high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial.
Insulin Use in Type 2 Diabetes and the Risk of Dementia: A Comparative Population-Based Cohort Study
Authors: Wajd Alkabbani, Colleen J. Maxwell, Ruth Ann Marrie, Suzanne L. Tyas, Iliana C. Lega, John-Michael Gamble
Journal: Diabetes Care (2023)

Objective Evidence of an increased dementia risk with insulin use in type 2 diabetes is weakened by confounding by indication and disease severity. Herein we reassess this association, while accounting for confounding through design and analysis. Research Design and Methods Using administrative health care data from British Columbia, Canada, we identified patients diagnosed with type 2 diabetes in 1998–2016. To adjust for confounding by diabetes severity through design, we compared new users of insulin to new users of a noninsulin class, both from a restricted cohort of those who previously received two noninsulin antihyperglycemic classes. We further adjusted for confounding using 1) conventional multivariable adjustment and 2) inverse probability of treatment weighting (IPTW) based on the high-dimensional propensity score algorithm. The hazard ratio [HR] (95% CI) of dementia was estimated using cause-specific hazards models with death as a competing risk. Results The analytical comparative cohort included 7,863 insulin versus 25,230 noninsulin users. At baseline, insulin users were more likely to have worse health indicators. A total of 78 dementia events occurred over a median (interquartile range) follow-up of 3.9 (5.9) years among insulin users, and 179 events occurred over 4.6 (4.4) years among noninsulin users. The HR (95% CI) of dementia for insulin use versus noninsulin use was 1.68 (1.29–2.20) before adjustment and 1.39 (1.05–1.86) after multivariable adjustment, which was further attenuated to 1.14 (0.81–1.60) after IPTW. Conclusions Among individuals with type 2 diabetes previously exposed to two noninsulin antihyperglycemic medications, no significant association was observed between insulin use and all-cause dementia.
Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody
Authors: Eva Mittler, Alexandra Serris, Emma S. Esterman, Catalina Florez, Laura C. Polanco, Cecilia M. O’Brien, Megan M. Slough, Janne Tynell, Remigius Gröning, Yan Sun, Dafna M. Abelson, Anna Z. Wec, Denise Haslwanter, Markus Keller, Chunyan Ye, Russel R. Bakken, Rohit K. Jangra, John M. Dye, Clas Ahlm, C. Garrett Rappazzo, Rainer G. Ulrich, Larry Zeitlin, James C. Geoghegan, Steven B. Bradfute, Simone Sidoli, Mattias N.E. Forsell, Tomas Strandin, Felix A. Rey, Andrew S. Herbert, Laura M. Walker, Kartik Chandran, Pablo Guardado-Calvo
Journal: Science Translational Medicine (2023)

Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus–experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb’s accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.
Increased PDGFRB and NF-κB signaling caused by highly prevalent somatic mutations in intracranial aneurysms
Authors: Yasuyuki Shima, Shota Sasagawa, Nakao Ota, Rieko Oyama, Minoru Tanaka, Mie Kubota-Sakashita, Hirochika Kawakami, Mika Kobayashi, Naoko Takubo, Atsuko Nakanishi Ozeki, Xiaoning Sun, Yeon-Jeong Kim, Yoichiro Kamatani, Koichi Matsuda, Kazuhiro Maejima, Masashi Fujita, Kosumo Noda, Hiroyasu Kamiyama, Rokuya Tanikawa, Motoo Nagane, Junji Shibahara, Toru Tanaka, Yoshiyuki Rikitake, Nobuko Mataga, Satoru Takahashi, Kenjiro Kosaki, Hideyuki Okano, Tomomi Furihata, Ryo Nakaki, Nobuyoshi Akimitsu, Youichiro Wada, Toshihisa Ohtsuka, Hiroki Kurihara, Hiroyuki Kamiguchi, Shigeo Okabe, Masato Nakafuku, Tadafumi Kato, Hidewaki Nakagawa, Nobuhito Saito, Hirofumi Nakatomi
Journal: Science Translational Medicine (2023)

Intracranial aneurysms (IAs) are a high-risk factor for life-threatening subarachnoid hemorrhage. Their etiology, however, remains mostly unknown at present. We conducted screening for sporadic somatic mutations in 65 IA tissues (54 saccular and 11 fusiform aneurysms) and paired blood samples by whole-exome and targeted deep sequencing. We identified sporadic mutations in multiple signaling genes and examined their impact on downstream signaling pathways and gene expression in vitro and an arterial dilatation model in mice in vivo. We identified 16 genes that were mutated in at least one IA case and found that these mutations were highly prevalent (92%: 60 of 65 IAs) among all IA cases examined. In particular, mutations in six genes (PDGFRB, AHNAK, OBSCN, RBM10, CACNA1E, and OR5P3), many of which are linked to NF-κB signaling, were found in both fusiform and saccular IAs at a high prevalence (43% of all IA cases examined). We found that mutant PDGFRBs constitutively activated ERK and NF-κB signaling, enhanced cell motility, and induced inflammation-related gene expression in vitro. Spatial transcriptomics also detected similar changes in vessels from patients with IA. Furthermore, virus-mediated overexpression of a mutant PDGFRB induced a fusiform-like dilatation of the basilar artery in mice, which was blocked by systemic administration of the tyrosine kinase inhibitor sunitinib. Collectively, this study reveals a high prevalence of somatic mutations in NF-κB signaling pathway-related genes in both fusiform and saccular IAs and opens a new avenue of research for developing pharmacological interventions.
Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor–induced colitis
Authors: Taylor M. Halsey, Anusha S. Thomas, Tomo Hayase, Weijie Ma, Hamzah Abu-Sbeih, Baohua Sun, Edwin Roger Parra, Zhi-Dong Jiang, Herbert L. DuPont, Christopher Sanchez, Rawan El-Himri, Alexandria Brown, Ivonne Flores, Lauren McDaniel, Miriam Ortega Turrubiates, Matthew Hensel, Dung Pham, Stephanie S. Watowich, Eiko Hayase, Chia-Chi Chang, Robert R. Jenq, Yinghong Wang
Journal: Science Translational Medicine (2023)

Immune checkpoint inhibitors (ICIs) target advanced malignancies with high efficacy but also predispose patients to immune-related adverse events like immune-mediated colitis (IMC). Given the association between gut bacteria with response to ICI therapy and subsequent IMC, fecal microbiota transplantation (FMT) represents a feasible way to manipulate microbial composition in patients, with a potential benefit for IMC. Here, we present a large case series of 12 patients with refractory IMC who underwent FMT from healthy donors as salvage therapy. All 12 patients had grade 3 or 4 ICI-related diarrhea or colitis that failed to respond to standard first-line (corticosteroids) and second-line immunosuppression (infliximab or vedolizumab). Ten patients (83%) achieved symptom improvement after FMT, and three patients (25%) required repeat FMT, two of whom had no subsequent response. At the end of the study, 92% achieved IMC clinical remission. 16 S rRNA sequencing of patient stool samples revealed that compositional differences between FMT donors and patients with IMC before FMT were associated with a complete response after FMT. Comparison of pre- and post-FMT stool samples in patients with complete responses showed significant increases in alpha diversity and increases in the abundances of Collinsella and Bifidobacterium , which were depleted in FMT responders before FMT. Histologically evaluable complete response patients also had decreases in select immune cells , including CD8 + T cells, in the colon after FMT when compared with non-complete response patients ( n = 4). This study validates FMT as an effective treatment strategy for IMC and gives insights into the microbial signatures that may play a critical role in FMT response.
<i>Fusobacterium</i> infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts
Authors: Ayako Muraoka, Miho Suzuki, Tomonari Hamaguchi, Shinya Watanabe, Kenta Iijima, Yoshiteru Murofushi, Keiko Shinjo, Satoko Osuka, Yumi Hariyama, Mikako Ito, Kinji Ohno, Tohru Kiyono, Satoru Kyo, Akira Iwase, Fumitaka Kikkawa, Hiroaki Kajiyama, Yutaka Kondo
Journal: Science Translational Medicine (2023)

Retrograde menstruation is a widely accepted cause of endometriosis. However, not all women who experience retrograde menstruation develop endometriosis, and the mechanisms underlying these observations are not yet understood. Here, we demonstrated a pathogenic role of Fusobacterium in the formation of ovarian endometriosis. In a cohort of women, 64% of patients with endometriosis but &lt;10% of controls were found to have Fusobacterium infiltration in the endometrium. Immunohistochemical and biochemical analyses revealed that activated transforming growth factor–β (TGF-β) signaling resulting from Fusobacterium infection of endometrial cells led to the transition from quiescent fibroblasts to transgelin (TAGLN)–positive myofibroblasts, which gained the ability to proliferate, adhere, and migrate in vitro. Fusobacterium inoculation in a syngeneic mouse model of endometriosis resulted in a marked increase in TAGLN-positive myofibroblasts and increased number and weight of endometriotic lesions. Furthermore, antibiotic treatment largely prevented establishment of endometriosis and reduced the number and weight of established endometriotic lesions in the mouse model. Our data support a mechanism for the pathogenesis of endometriosis via Fusobacterium infection and suggest that eradication of this bacterium could be an approach to treat endometriosis.
Clinical, Imaging, and Histopathological Features of Pulmonary Sequelae after Mild COVID-19
Authors: Daniel Gagiannis, Carsten Hackenbroch, Wilhelm Bloch, Fabian Zech, Frank Kirchhoff, Sonja Djudjaj, Saskia von Stillfried, Roman Bülow, Peter Boor, Konrad Steinestel
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Clinical, Imaging, and Histopathological Features of Pulmonary Sequelae Following Mild COVID-19." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.